Division of Oncology, Department of Medicine, Washington University in Saint Louis, St. Louis, MO, USA.
Division of Multiple Myeloma, Department of Hematology & Hematopoietic Transplantation, City of Hope, Duarte, CA, USA.
Ann Hematol. 2024 Nov;103(11):4557-4565. doi: 10.1007/s00277-024-05975-7. Epub 2024 Sep 4.
Patients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study.
PATIENTS/METHODS: Patients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10 mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m. Methylprednisolone was administered as 125 mg on day 1 and prednisone 60 mg days 2-4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response.
Fifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9-4.1 months).
We demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients.
This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.
患有三药难治性（TCR）多发性骨髓瘤（MM）的患者通常需要细胞减灭化疗以快速控制疾病。苯达莫司汀是一种可在门诊使用的双功能烷化剂，伊沙妥昔单抗是一种具有独特细胞毒性特征的抗 CD38 单克隆抗体。我们假设伊沙妥昔单抗-苯达莫司汀-泼尼松将是 TCR MM 的一种耐受良好的方案，并进行了单中心、Ib 期、研究者发起的研究。
患者/方法：患者患有 TCR MM，且上次接受达雷妥尤单抗治疗的时间超过 6 周。本研究采用 3+3 设计，以确定最大耐受剂量（MTD）和/或推荐的 II 期剂量（RP2D）。伊沙妥昔单抗 10 mg/kg 静脉输注，每周一次（第 1 周期），此后每 2 周一次。苯达莫司汀在 3 个剂量水平（DL）：50、75 和 100 mg/m 上于第 1 和第 2 天给药。第 1 天给予甲泼尼龙 125mg，第 2-4 天给予泼尼松 60mg。使用常见的定义来评估剂量限制毒性（DLT）、不良事件（CTCAE v 5.0）和疾病反应。
共治疗了 15 名患者（3 个 DL1、6 个 DL2、6 个 DL3）。中位年龄为 71 岁，53%的患者具有高危细胞遗传学特征，34%的患者具有既往 BCMA 靶向治疗史。在 DL2 观察到 1 例 DLT（3 级血小板减少症伴出血）。无 5 级与治疗相关的 AE。未达到 MTD。总体缓解率为 20%（15 名患者中的 3 名），包括 1 例严格意义的完全缓解。中位 PFS 为 2.5 个月（95%CI 0.9-4.1 个月）。
我们证明了伊沙妥昔单抗-苯达莫司汀-泼尼松的安全性和耐受性。毒性轻微，干预有限，易于管理。由于入组缓慢，该研究被终止。然而，我们观察到即使在高度难治性患者中也有应答。
本研究于 2019 年 9 月 6 日在 clinicaltrials.gov 上注册，编号为 NCT04083898。
